This invention relates to a lubricating composition for use with biomedical devices. More particularly, this invention relates to an injectable emulsion capable of being used within human arteries during a rotational atherectomy procedure that both lubricates the atherectomy device and is capable of acting as a drug carrier.
It is well known that, for various reasons, humans can develop a condition in which a type of plaque or hard deposit builds up along the walls of the blood vessels, thereby partially blocking the blood flow and causing severe medical conditions. Several different procedures have been developed for dealing with this situation. One such procedure is rotational atherectomy, in which a rotary mechanical system removes relatively hard intravascular deposits from the walls of human arteries by differentially cutting away the inelastic, hardened deposits while sparing the soft, elastic tissue of the inner lining of the human blood vessels. The seminal patent that discloses a device for performing this procedure is U.S. Pat. No. 4,990,134 (Auth) entitled xe2x80x9cTRANSLUMINAL MICRODISSECTION DEVICE,xe2x80x9d the disclosure of which is incorporated herein by reference.
In the commercially available device described in U.S. Pat. No. 4,990,134, known as the Rotablator(copyright), an ellipsoidal burr coated with tiny diamond chips is rotated at a speed of at least approximately 155,000 revolutions per minute. The burr is connected to a drive motor capable of high speed rotation via a hollow, flexible, helically-wound drive shaft, and is routed through the blood vessel over a narrow guide wire that extends through the central bore of the burr and its drive shaft. When this device is operated, the burr preferentially cuts hard, inelastic material (plaque) while sparing soft, elastic material (tissue) and generates microscopic debris fragments that are sufficiently small in size so as to pass through even the narrowest vascular channels (capillary beds) without clogging them.
This Rotablator(copyright) atherectomy device, as well as any other microdissection device that involves rotational ablation, necessarily generates thermal energy during its rotation. For this reason, as disclosed in U.S. Pat. No. 4,990,134, a biocompatible saline solution is infused through a plastic sheath within which the drive shaft rotates, to cool the sliding interface during operation.
In addition to performing a cooling function, some lubrication is needed to prevent wear caused by rotational friction between the guide wire and the drive shaft or between the drive shaft and the plastic sheath. The major factors that affect wear in this type of rotational contact are load, temperature, surface speed, surface finish, surface hardness, contact area, time, and the type, amount, and viscosity of the lubricant.
During extended operation of the device, however, additional lubrication should be provided to sustain the performance of the guide wire, the drive shaft, and the sheath. Such a lubricant, if infused through the device from outside the patient""s body, must of course, be non-toxic and safe for arterial use. In addition, to be effective in use with the Rotablator(copyright) advancer/guide wire system, the lubricant should be able to withstand shear stresses at 50xc2x0 C. and should not promote the agglomeration of ablated plaque particles.
Injectable oil-in-water emulsions are currently being used for two clinical applications. The first is for parenteral or intravenous nutrition, as a source of fat calories and essential fatty acids. Examples include Intralipid(copyright), available from Pharmacia and Upjohn, and Liposyn(copyright), available from Abbott Laboratories. Emulsions are also being used as a vehicle for poorly water-soluble lipophilic drugs that cannot be injected directly. Examples include Diprivan(copyright), containing the anesthetic drug propofol, and Diazemuls(copyright), containing the drug diazepam.
Lipid emulsions are inherently unstable. No commercially available lipid emulsion is stable following dilution in physiological (0.9% w/v) salt solution. This instability is manifested by formation of large droplets of non-emulsified oil on the surface as well as by a shift in droplet size distribution towards much larger diameters. Such changes often occur within the first hour following dilution in saline and are accelerated by heating or by applying any shear force. The relatively low pH and high ionic strength of saline contributes to this effect.
Commercial lipid emulsions separate into oil and water layers upon thawing after storage at freezing temperatures. For this reason, special care must be taken when shipping in winter through geographic areas having below freezing temperatures. It is preferred that the lubricant be an emulsion which is stable in saline and stable upon freezing with subsequent thawing. The present invention meets these needs and overcomes other deficiencies in the prior art.
What would be desirable is an improved, pharmacologically compatible medical lubricant that is capable of delivering therapeutic agents to target locations within the body. What has not been provided in the prior art is an injectable medical lubricant suitable for lubricating, rotating, and otherwise moving medical devices, where the lubricant can optionally act as a carrier for therapeutic agents to thereby yield a therapeutic effect to a treatment site in the body.
The present invention includes a medical lubricant suitable for injection into a patient. The lubricant is an oil-in-water emulsion including an oil, a surfactant, a co-surfactant and water. The lubricant preferably also includes a cryogenic agent, a pH buffer, and a preservative. The lipid emulsion preferably has a mean particle or droplet diameter of less then 1 micrometer, most preferably less than about 0.5 micrometer. The lubricant can be subjected to substantial shear by a rotating member, exhibits a commercially acceptable shelf life during storage under ambient temperatures, and is able to withstand freeze-thaw cycles without substantial degradation. The lubricant can be diluted in physiological saline for injection and maintains suitable emulsion droplet size after such dilution.
The oil can be a vegetable oil or a medium chain triglyceride. The preferred oil is refined olive oil, which preferably comprises mostly mono-unsaturated oleic acid. The oil can lubricate medical devices, such as rotating drive shafts in atherectomy devices, thereby reducing wear on moving parts. A mean droplet size of less than about 1 micrometer allows injection into the bloodstream and subsequent absorption by the body without ill effect. The emulsion most preferably includes about 20 g refined olive oil per 100 mL emulsion.
The surfactant can be a phospholipid, preferably purified egg yolk phospholipids. The surfactant stabilizes the oil droplets dispersed in the continuous aqueous phase. The present invention preferably includes about 1.2 g egg yolk phospholipids per 100 mL emulsion.
The co-surfactant can be a salt of a bile acid, most preferably sodium deoxycholate. The co-surfactant significantly improves droplet stability after saline dilution, heating, and exposure to high shear forces. Droplet stability includes the resistance to formation of larger droplets, creaming, and formation of a separate oil layer. Bile salt, acting in conjunction with glycerin, provides improved freeze-thaw stability. Applicants believe the bile salt also improves lubricity by acting as a wetting agent, improving the coating of moving metal parts. The present invention most preferably includes about 0.4 g bile salt per 100 mL emulsion.
The cryogenic agent can be refined propylene glycol or glycerin, preferably glycerin. Glycerin also provides improved lubricity. The present invention preferably includes about 10 g glycerin per 100 mL emulsion.
The pH buffer imparts improved droplet stability in a saline diluent. Any physiological pH buffer may be used. When the pH buffer is an amino acid buffer, said amino acid buffer usually has a concentration of less than 0.20 g/100 mL emulsion. The amino acid buffer is most preferably L-histidine in a concentration of about 0.16 g per 100 mL emulsion.
The preservative is preferably a heavy metal chelator such as disodium EDTA. EDTA, and the histidine buffer, serve as antioxidants, protecting unsaturated fatty acids found in egg yolk phospholipids. The antioxidants provide an extended shelf life for the emulsion at room temperature and inhibit peroxide formation during clinical use. Disodium EDTA is preferably present in about 0.014 g per 100 mL emulsion.
The emulsion preferably has the pH adjusted to between about 8.3 and 8.8, with a base such as sodium hydroxide. This pH range optimizes the emulsion stability in the presence of non-buffered saline, which is slightly acidic. Sodium hydroxide can be present in about 3.0 mEq per liter of emulsion.
An emulsion according to the present invention can be prepared by combining refined olive oil, 1.2% egg yolk phospholipid, 0.16% L-histidine (10 mM), 0.014% disodium EDTA (0.5 mM), and water, followed by ultrasonic processing for about 15 minutes. The emulsion can also be prepared using high pressure homogenization techniques well known to those skilled in the art.
In use, the emulsion can be stored for at least eighteen (18) months, preferably twenty-four (24) months at room temperature. The emulsion can be stored frozen at xe2x88x9230xc2x0 C., and then thawed without causing significant changes in droplet size distribution. The emulsion can be added to normal, unbuffered 0.9% saline solution. One anticipated use is injection of the emulsion into an IV bag of saline, thereby diluting the emulsion. The diluted emulsion can be infused from the IV bag through a catheter tube housing a rotating member, such as an atherectomy drive shaft or an ultrasonic probe drive shaft. The emulsion serves to lubricate the moving parts and can thereafter enter the blood stream of a patient without ill effect.
In certain embodiments of the invention, the above described medical lubricant additionally includes one or more therapeutic agents to thereby provide a therapeutic effect to a treatment site in the body. One or more of the therapeutic agents may include a genetic material encoding a therapeutic agent, a non-genetic therapeutic material, proteins or cells that produce a therapeutic effect. The choice of therapeutic agent will depend on the application. In one embodiment where the lubricant is used in conjunction with an atherectomy device, one or more of the therapeutic agents inhibits cell proliferation and provides an anti-restenosis effect. In other embodiments where the lubricant is used in conjunction with a transmyocardial revascularization (TMR) device or percutaneous myocardial revascularization (PMR) device, one or more of the therapeutic agents promotes angiogenesis.
In yet another aspect of the invention, a method is provided for lubricating an intravascular device. The inventive method involves first preparing a patient for a medical procedure and then inserting into the patient a medical device that is in need of lubrication. A medical oil emulsion lubricant is infused into the patient during the insertion and/or operation of the medical device. The medical oil emulsion lubricant contains olive oil, an egg yolk phospholipid, a bile salt, an amino acid buffer, and a desired therapeutic agent. In one embodiment of the method the medical procedure is atherectomy and the medical device is an intravascular device that is capable of differentially removing intravascular deposits from the walls of an artery. During the atherectomy procedure, the therapeutic agent present in the medical oil emulsion lubricant usually contains a cell proliferation inhibitor that provides an anti-restenosis effect. In another embodiment of the lubrication method, the medical procedure is myocardial revascularization and the medical device is a myocardial revascularization device. During the myocardial revascularization procedure it is usual to include in the medical lubricant a therapeutic agent that promotes angiogenesis.